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Solid-phase synthesis method of degarelix

A solid-phase synthesis, degarelix technology, applied in the preparation methods of peptides, chemical instruments and methods, organic chemistry, etc., can solve the problems of easy introduction of heavy metal substances, easy shedding, breakage at the joint between peptides and resins, etc. Reduce damage to human body, avoid rearrangement reactions, and have little effect on human body and environment

Active Publication Date: 2014-08-20
NANTONG SHIMEIKANG PHARMA CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The Trt protecting group on the side chain needs to be removed by TFA. During the acid removal process, the Boc protecting group on the ILys side chain is easy to fall off. In addition, the link between the peptide and the resin is also prone to breakage during TFA treatment.
It is easy to introduce heavy metal substances when the Alloc protecting group on the side chain is removed, which is not suitable for drug synthesis

Method used

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  • Solid-phase synthesis method of degarelix
  • Solid-phase synthesis method of degarelix
  • Solid-phase synthesis method of degarelix

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1: Preparation of Fmoc-D-Ala-Rink-Amide-MBHA.

[0036] Weigh 0.88g (0.3mmol) Fmoc-Rink-Amide-MBHA resin (degree of substitution 0.34mmol / g) into a 20ml BD syringe with a frit (ordinary glass peptide reactor can also), use 3 times the resin volume of DCM Swell twice, 1 hour each time, after the resin is completely swollen, use 20% (v / v) piperidine / DMF solution to remove the Fmoc protecting group twice for 5 min and 20 min respectively, and wash with DMF 3 times. Dissolve 373.56mg (1.2mmol) Fmoc-D-Ala-OH and 162.12mg (1.2mmol) HOBt with 10ml DMF, ice bath for ten minutes, add 0.4ml (2.4mmol) DIEA, activate for 3min, then add 455.04mg (1.2mmol) ) HBTU, the mixed solution was added to the solid-phase reactor, and the reaction was stirred for 2 h. The ninhydrin test was negative, washed three times with DMF, and drained to obtain Fmoc-D-Ala-Rink-Amide-MBHA.

Embodiment 2

[0037] Example 2: Fmoc-D-2Nal-D-Phe(4Cl)-D-3Pal-Ser(tBu)-4Aph(ivDde)-D-4Aph(tBuCbm)-Leu-ILys(Boc)-Pro-D-Ala - Synthesis of Rink-Amide-MBHA.

[0038] Fmoc-D-Ala-Rink-Amide-MBHA (0.3 mmol) was charged into the solid phase reactor, washed twice with DMF, and the Fmoc protecting group was removed twice with 20% (v / v) piperidine / DMF solution, time 5min and 20min respectively, washed 3 times with DMF, and tested by ninhydrin method. Dissolve 404.88mg (1.2mmol) Fmoc-Pro-OH and 162.12mg (1.2mmol) HOBt with 10ml DMF, ice bath for ten minutes, add 0.4ml (2.4mmol) DIEA, activate for 3min, then add 455.04mg (1.2mmol) HBTU , the mixed solution was added to the solid-phase reactor, and the reaction was stirred for 1.5h. The ninhydrin test was negative, and the DMF was washed three times.

[0039] Repeat the above operation, according to the amino acid sequence of degarelix, connect Fmoc-Pro-OH, Fmoc-ILys(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-4Aph(tBuCbm)-OH, Fmoc-4Aph( ivDde)-OH, Fmoc-Ser(tBu)-OH...

Embodiment 3

[0043] Example 3: AC-D-2Nal-D-Phe(4Cl)-D-3Pal-Ser(tBu)-4Aph(ivDde)-D-4Aph(tBuCbm)-Leu-ILys(Boc)-Pro-D-Ala - Synthesis of Rink-Amide-MBHA.

[0044] Fmoc-D-2Nal-D-Phe(4Cl)-D-3Pal-Ser(tBu)-4Aph(ivDde)-D-4Aph(tBuCbm)-Leu-ILys(Boc)-Pro-D-Ala-Rink- Amide-MBHA was loaded into the solid phase reactor, washed twice with DMF, deprotected Fmoc twice with 20% (v / v) piperidine / DMF solution for 5 min and 20 min respectively, washed 3 times with DMF, ninhydrin law test. Then, a mixed solution of acetic anhydride (3 ml) and DCM (9 ml) was added, and the reaction was stirred for 30 min, washed three times with DMF, and detected by ninhydrin detection method.

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Abstract

The invention discloses a solid-phase synthesis method of degarelix. The solid-phase synthesis method of degarelix comprises the following steps: on the basis of taking Fmoc-amino resin as a solid-phase carrier, replacing orotic acid fragments connected with an alanine benzene ring in the fifth site and an amino in the fourth site with ivdde, and performing sequential condensation reaction from the end C to the end N so as to connect 10 protected amino acids, thereby obtaining a full-protective peptide resin; then removing the Fmoc protecting group of end N D-Nal, acetylating by using acetic anhydride and pyridine, replacing ivDde with Hor, cutting the peptide resin by using a splitting agent, and precipitating by using frozen diethyl ether to obtain crude peptide. Besides, the invention also relates to a method for synthesizing a raw material Fmoc-Aph(ivDde)-OH by use of ivDde-OH and Fmoc-Aph-OH. The solid-phase synthesis method of degarelix has the advantages that the ivDde is introduced to synthesize decapeptide firstly and then the Hor is used as a substitute to avoid a rearrangement side reaction; the solid-phase synthesis method is simple in process steps, easy to control, low in influence on a human body and the environment, high in yield, and suitable for large-scale production.

Description

technical field [0001] The present invention relates to a solid-phase synthesis method of degarelix. Background technique [0002] Degarelix, with the trade name of Firmagon, is a degarelix powder injection developed by Ferring Pharmaceuticals, which was approved by the FDA and launched in the United States on December 24, 2008. Indications: FIRMAGON is a GnRH receptor antagonist for the treatment of advanced prostate cancer. Degarelix is ​​a gonadotropin-releasing hormone (GnRH) receptor inhibitor drug that reversibly inhibits the pituitary GnRH receptor to reduce the release of gonadotropins and then inhibit the release of testosterone. Degarelix slows the growth and progression of prostate cancer by inhibiting testosterone, which is essential for the continued growth of prostate cancer. Hormone therapy for prostate cancer to lower testosterone levels initially resulted in a surge in testosterone levels. This initial stimulation of the hormone receptor temporarily promot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/06C07K1/04
CPCY02P20/55
Inventor 董守良曹硕李兆亮葛鑫
Owner NANTONG SHIMEIKANG PHARMA CHEM
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